New COX-2/5-LOX inhibitors: apoptosis-inducing agents potentially useful in prostate cancer chemotherapy

J Med Chem. 2004 Dec 2;47(25):6195-206. doi: 10.1021/jm0407761.

Abstract

The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Arachidonate 5-Lipoxygenase / chemistry
  • CHO Cells
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetinae
  • Cyclooxygenase 2
  • Drug Screening Assays, Antitumor
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / chemistry
  • Lipoxygenase Inhibitors*
  • Male
  • Membrane Proteins
  • Models, Molecular
  • Prostaglandin-Endoperoxide Synthases / chemistry
  • Prostatic Neoplasms / drug therapy
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Isoenzymes
  • Lipoxygenase Inhibitors
  • Membrane Proteins
  • Pyrazoles
  • Arachidonate 5-Lipoxygenase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases